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Circulation on the Run

May 25, 2020

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary, and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: I'm Greg Hundley, Associate Editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Today's feature discussion is the first huge look at the global, regional and national burden of calcific aortic valve disease and degenerative mitral valve disease over a huge period, from 1990 to 2017. Very important discussion coming right up after this coffee chat.

Greg, do you mind if I go first?

Dr Greg Hundley: Go ahead, Carolyn.

Dr Carolyn Lam: The first paper I want to talk about applies novel single cell transcriptomics to unveil new insights into pressure overload cardiac hypertrophy. Here's your quiz, Greg, ready?

Dr Greg Hundley: Well, I'm choking on my coffee here, but go ahead.

Dr Carolyn Lam: All right, I was thinking of asking you about single cell transcriptomics but let me just tell you the results. Single cell RNA sequencing is a new and rapidly advancing technique that can comprehensively characterize gene expression and relationships among individual cells.

Dr Wang from Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, and Peking Union Medical College and colleagues analyze the transcriptomes of 11,492 single cells and identified major cell types, including both cardiomyocytes and non-cardiomyocytes based on their molecular signatures. They did this at different stages during the progression of pressure overload induced cardiac hypertrophy in a mouse model.

Their findings not only illustrated dynamically changing cell type crosstalk doing pathological cardiac hypertrophy, but also shed light on strategies for cell type and stage specific interventions in cardiac disease. For example, subtype switching of macrophages was found to be a key event underlying the transition from normal to decline dejection fraction in cardiac hypertrophy.

Thus, targeting macrophages in hypertrophy for example, during the switch could attenuate disease progression. All of this is discussed in an editorial by doctors, Zhang and Zhou from University of Alabama in Birmingham.

Dr Greg Hundley: Oh wow. Carolyn very important macrophage infiltration and another role for those, that cell type. Well, my first paper gets at the topic of reversal of these factor Xa inhibitors.

In this particular patient population, it's the situation where we're dealing with intracranial hemorrhage. The article comes from Dr G Morgan Jones and colleagues from the University of Tennessee Health Sciences Center. Since the approval of oral factor Xa inhibitors, there have been few papers published really regarding the ability to neutralize the anti-coagulate effects of these agents, particularly after intercranial hemorrhage.

Dr Carolyn, this is a multi-center, retrospective, observational cohort study of 433 patients. Then it received apixaban, or rivaroxaban, and then developed an intercranial hemorrhage. They then subsequently received prothrombin complex concentrates in that period of time between 2015 and 2019.

Dr Carolyn Lam: Wow. How did these participants who had intracranial hemorrhage, how did they fare after receiving these prothrombin concentrates?

Dr Greg Hundley: Yeah, well, administration of the prothrombin complex concentrates after, apixaban or rivaroxaban in the setting of intracranial hemorrhage, provided a high rate of excellent or good hemostasis. That was in nearly 82%, coupled with an adverse consequence of 3.8% of those experiencing a thrombosis.

Thrombosis occurred in 25 patients who had a total of 26 thrombotic events of which 22 occurred in the first 14 days, following the prothrombin complex concentrate administration. One patient had documentation of an infusion related reaction. For the full cohort of patients, in the hospital mortality was 19% and the median ICU care and hospital length of stay were two and six days respectively.

Carolyn, these cohort analyses seemed to demonstrate the possibility of success and similar to other observational cohort studies. The results of this study suggest that future randomized control trials evaluating the clinical efficacy of these prothrombin complex concentrates in patients with factor Xa inhibitor related intercranial hemorrhage are needed.

Dr Carolyn Lam: Nice, Greg. You know what? I'm going to start with a quiz. True or false, heart failure with reduced ejection fraction is characterized by blunting of the positive relationship between heart rate and left ventricular contractility known as the force frequency relationship?

Dr Greg Hundley: Well, Carolyn, this is one of those where if I go 50/50, you'll knock out the wrong answer. Let's say, I'm going to go, true.

Dr Carolyn Lam: You're so right, Greg. This next paper really deals with this. It's from corresponding author, Dr Witt from Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds in UK and colleagues who previously described that, tailoring the rate responsive programming of cardiac implantable electronic devices in patients with HFrEF based upon individuals noninvasive force frequency relationship data, really improves exercise capacity. Addressing this reduce force frequency relationship and HFrEF.

 Now in the current paper, they sought to examine whether using force frequency relationship data to tailor heart rate response in HFrEF with inpatients, with HFrEF and cardiac implantable electronic devices would favorably influence exercise capacity and left ventricular function six months later.

They conducted a single center, double blind, randomized parallel group trial in 83 patients with HFrEF. With a cardiac implantable electronic device and randomized to tailored rate response programming based on these individuals force frequency relationship versus conventional age guided rate response programming. The primary outcome measure was changed in walk time on a treadmill walk test.

Dr Greg Hundley: Wow, Carolyn. So this is a really detailed analysis. What did they find?

Dr Carolyn Lam: They found that rate adaptive cardiac implantable electronic device programming taking into account the at normal force frequency relationship in these patients, was associated with improved exercise time.

Force frequency relationship guided heart rate settings had no adverse effects on left ventricular structure and function. While conventional settings were associated with a reduction in left ventricular ejection fraction.

Out of the box age guided rate adaptive pacing, might be a sub optimal choice in patients with heart failure and an assessment of the force frequency relationship might be of clinical benefit in facilitating personalized rate adaptive programming.

Dr Greg Hundley: Very nice.

Dr Carolyn Lam: Thanks Greg, but there's other stuff I want to tell you about in this issue. There's a research letter by Dr Gambier on Molecular Imaging of Infective Endocarditis with Floral Multiple Trials PET-CT. This is the first time that a Florine 18 PET tracer has been used to specifically image bacterial infection of the heart valves with high sensitivity and specificity in an animal model.

Dr Greg Hundley: Oh, good job, Carolyn. Those flooring tracers, very interesting. Another application perhaps. Well, in a perspective piece, I have an article Carolyn from Dr Orly Vardeny from University of Minnesota Medical School in Minneapolis and remembers the prior cardiovascular complications from influenza. And how those experiences may be useful in anticipating some of the cardiovascular complications that we may see from SARS-CoV-2.

In a separate article, Dr Aatish Garg and collaborators from VCU Health, present an ECG case of syncope in an individual with severe aortic stenosis status post bioprosthetic aortic valve replacement and coronary artery bypass grassing. Who also has paroxysmal AV block?

Then finally, Carolyn, Professor Concepcion Peiró from Universidad Autónoma in Madrid. Has an on my mind pace discusses ACE inhibition and our abuse in relation to the SARS-CoV-2 to virus bonding to ACE two binding sites within the respiratory epithelium.

Well, Carolyn, how about we get on to that feature discussion? I can't wait to hear about aortic and mitral valve disease over nearly 30 years.

Dr Carolyn Lam: Let's go Greg. Nondramatic valvular heart disease is really common throughout the world. However, no studies have previously estimated their global or national burden, that is until today's feature paper. That's part of the Global Burden of Disease, or GBD, 2017 study. I am so pleased to have with us a corresponding author, Dr Greg Roth from University of Washington. As well as Victoria Delgado, our associate editor from Leighton University Medical Center.

What a great topic to discuss. Nondramatic valvular heart disease, meaning calcific aortic valve disease, degenerative module valve disease, all the stuff we see and have to deal with now. Greg, could you please tell us about this GBD effort and really what you found?

Dr Greg Roth: Let me tell you a little bit about the Global Burden of Disease Study and then why we wanted to explore this question and then what we found. I am the lead for cardiovascular research at the Institute for Health Metrics and Evaluation in Seattle at the University of Washington. We're the coordinating center for the Global Burden of Disease Study. It's now in its second decade, and it's a large-scale effort to quantify the lost health due to early death and disability for every country in the world.

This is a huge effort with over 5,000 people around the world working on it. We work closely with governments around the world, as well as the World Health Organization, as well as county, state, and other authorities in the US.

Our goal is really to bring together all of the evidence in the world to bear on important health policy questions. One of the areas that I've had a long interest in is valve disease.

I'm a practicing cardiologist at our county hospital here in Seattle, as well as an echocardiographer. I was really excited by the idea of bringing together my passion for taking care of patients with valve disease and looking at how to use diagnostic imaging to take better care of them and the disease modeling research that I do at the institute.

We decided a couple of years ago after exploring the global patterns of rheumatic heart disease, that we would turn our focus towards these really important questions of non-rheumatic valve disease. There's obviously a very large literature and lots of active research around the clinical pathways that we need to follow for patients with calcific valve disease and mitral valve disease that's not due to rheumatic causes. Obviously in recent years, we've got amazing technologies and interventions that we're using more and more frequently like percutaneous interventions.

However, we had not done the work to turn this really interesting tool, the Global Burden of Disease Study, towards looking at these important causes. We pulled together every data source we could find on the population level burden of nonrheumatic valve disease and then using a range of techniques, and we rely heavily on tools that come out of data science.

These include computer disease modeling tools that we've developed as well as ensemble models and other sort of big data approaches to pull all of this together into comparable, consistent estimates of death and prevalence. Then we're also really interested in using those to estimate what we call summary metrics of health, like disability adjusted life years. We do this for a very long time series. So we went back all the way to 1990 and we looked all the way to 2017.

Then we're able to get a really good sense of not only what the impact of these diseases are, but how they compare to the 350 other diseases that we estimated in exactly the same way for the Global Burden of Disease Study. Also, where is the burden of these particular conditions going up? Where is it going down?

We're really excited to be able to pull that together into this paper. In which we report the global, regional, and national burdens of calcific aortic valve disease and degenerative mitral valve disease. As well as a right sided valve disease that's not due to congenital endocarditis causes, which we estimate separately in the study.

Dr Carolyn Lam: Greg, you say, you're excited. I can definitely speak, I think on behalf of both Victoria and Augie, that we're the ones excited publishing this really great piece of work here in circulation. You know personally, I'm a great fan of your work in GBD. Tell us the results.

Dr Greg Roth:  What we found was that in 2017, there was an estimated 12.6 million cases of calcific aortic valve disease in the world and 18.1 million cases of degenerative valve disease globally. With higher rates of calcific valve disease, among men and higher rates of degenerative valve disease among women. Now that is an aggregate.

We've produced estimates for every country in the world and for larger countries with more than 200 million people, we've gone down to what we call the first administrative level. So, US states, Chinese provinces, and we do this in the larger countries, but when you add it all up, you get those numbers.

We also found that there were just over a hundred thousand deaths globally each year due to calcific aortic valve disease and about 35,000 deaths reported due to degenerative mitral valve disease. I think this is really interesting because of course, as clinicians, we have a lot of experience with sources like cohort studies, and trials, and registries, but we have not actually looked at what's actually the world's largest public health reporting system, which is vital registration, meaning death certificates.

Now, most of us have filled out that certificates and we always wonder, how reliable are there? And there's clearly limitations. In fact, a huge amount of our work at the Global Burden of Disease Study is dealing with the limitations of death certificates, looking for bias, and adjusting that bias when we can, but these are death certificates where somebody's entered these causes as the underlying cause of death.

I think when that actually shows up on a death certificate, that's actually a real signal to us that there was a physician out there who felt pretty strongly that that was the sort of trigger that led to the patient's death.

We also found that aging and population growth are leading to about a hundred percent increase over this period of time over the last 25 years in the number of deaths due to these nonrheumatic valve diseases. If we age standardized, we see that the trend is flat, but if you're running a health system or a minister of health, you need to hear that message that with aging and population growth affecting almost every country in the world, you're going to see dramatic rises in the number of cases of both of these conditions showing up on the doorstep of all of your hospitals.

Dr Carolyn Lam: Fantastic Victoria, could you put these findings in context for us and maybe take us behind the scenes a little bit at what the editors thought?

Dr Victoria Delgado: These are very important data, because so far, for example, we have, as Greg said, registries and one of the most known registries was for example, in Europe, The Valvular Heart Survey that was done in 2001, if I remember well. Has been redone recently, it was last year published in circulation. The other one with a very large data is coming from counties. With similar data to the results that are publishing now.

For example, if you compare those two registries with much smaller populations, in US, they always report much, much frequently the genetic mitral valve regurgitation. While in Europe, aortic stenosis is the most frequent one, calcific aortic stenosis. Here, I was again surprised with in the global population that again, degenerative mitral valve regurgitation is much more prevalent than calcific aortic stenosis, but you can see that there was an increase of 124% in the prevalence of calcific aortic valve disease in 2017.

I wonder if this is related to the awareness of the risk associated with aortic stenosis and they invent of a new therapies, transcatheter therapies, with the TAVI for example, or transcatheter aortic valve replacement, which has opened the door for an effective treatment for many patients that before were simply denied for surgery. I don't know if you have further insights into that.

Dr Greg Roth: Yes. I think that's a really important point, that we see a lot of variation in the data. While we have millions of death certificates to look at all around the world. Really scores of millions, where we can look for trends and patterns. The population level data on nonrheumatic valve disease is actually quite limited compared to most diseases.

We did a very aggressive perspective review of the published and gray literature and found about 50 sources reporting prevalence for these conditions that were usable in our study. For the most part, those studies are not long time series. We have to estimate trends, piecing together data from different populations.

Now, there are a couple of places in the world where you can get a long trend of time where they've gone back repeatedly in the same population and looked with echo, which you obviously need here to make these diagnoses.

As far as we can tell, and these are just a handful of studies, the trend is flat. We don't see large increases. Now, the increases in our study were completely driven by aging and population growth and the age standardized rates. The epidemiologic pattern for this disease is that it's flat and for mitral valve disease, maybe trending down a little bit.

I think it's clear that in places where there's been a lot of attention paid either because of new therapies, like TAVR or new access to diagnostic screening with the growth of echo cardiography and other screening methods, that is a limitation of the study, for sure. I think what it really focuses me on is the idea that we need better data. We need to think about ways and probably more cost effective ways of surveilling for these conditions, but I'll tell you something that was really interesting, that we found is that, in the United States where we relied heavily on administratively coded data, because we have that in a uniform format for every state and we have a long time series for that, and we have complete vital registration.

We looked at the state level and we found that the all ages rate, was actually going up. Meaning it wasn't just population growth and aging, but in about a third of the states, the true epidemiologic rate of the disease was going up. Meaning it's becoming more common even if you control for the change in age structure of a country like the United States over time.

I think that given the fact that we're seeing this explosion of obesity around the world, and we know that atherosclerotic risk factors can be a major driver of let's say calcific aortic valve disease. I mean, an interesting question is, is valve disease going to be sort of a canary in the coal mine? Are we going to see more of it at younger ages?

Traditionally it's been the oldest patients who actually survived the longest and tend to be healthier, who we can actually find having the disease, but I wonder, are we going to see more of that as patients present with more obesity. Unfortunately we know that reversing or controlling those atherosclerotic risk factors hasn't paid off in big ways for preventing calcific aortic valve disease. It's complex and like mitral valve disease, clearly there's likely to be a very strong genetic component as well.

Dr Carolyn Lam: Greg, you mentioned a little bit more about the age effect, but you did mention some sex differences. Could you just clarify a little bit about that and maybe the interaction between the two?

Dr Greg Roth: What we've all been taught, or at least what I was always taught, was that there was more mitral valve disease in women. We actually did find that in the study and that was reassuring because when we went back to look for the source of that sort of common teaching, actually, it's pretty hard to find.

I think it actually comes, my guess is, from a lot of people's clinical practice. To see that match-up between what we thought was going to be true in terms of the relative prevalence by sex for these two major diseases, calcific aortic valve disease and degenerative mitral valve disease was reassuring. It suggested that the data we have is actually picking up on real patterns and patterns that match sort of our clinical experience as well.

One of the interesting things about the interaction between age and sex, is that women live much longer on average than men. As women age into those oldest years, what we actually see is a decline in the burden of disease. There's an increase in stroke, but for everything else, those women are truly survivors. Actually we see less bowel disease and cardiovascular disease in general, in the oldest old women.

What we do see is a massive rise in cognitive impairment and dementia. That's a very active area of research for us right now. The interaction between atherosclerotic risks, which can drive things like valve disease and of course, coronary disease and stroke and then the cognitive impact is a really important area of research. There are a couple of great papers that have come out even just in the last few weeks.

I think this question of how risk is going to impact people in those oldest age groups? Is really important. We know the population is aging. We know that in some places, life expectancy is increasing to the point where we really need to rethink what the disease patterns are going to be in the oldest old.

Dr Carolyn Lam: Indeed. So the feminization of aging is kind of what I like to call it, but yikes Victoria. Could I maybe ask you to please give the final words of advice and maybe the take home messages?

Dr Victoria Delgado: I think that this data are really welcomed because as Greg said, we need to understand better how we can modify the prognosis of these prevalent and how we can tackle it and for that we need data. I think that these are very welcomed data.

Now, how we are going to do it in the future? That's a great question. I don't have the answer right now, but I think that increasing the awareness that nonrheumatic valvular heart disease can impact as well on the outcomes of the population, is important to know. I think that people need to have access to diagnostics best particularly echo cardiography is very available imaging technique and very feasible. We can have right now developments where we can do the echo cardiography with our phone by adding one of the probes.

I think that in the future, we may see more and more valvular heart disease that probably was already there, but we just need to increase the awareness. From those data, learn how we can treat those individuals if they need and how we can improve the outcome of these individuals.

Dr Carolyn Lam: Thank you, Victoria. Thank you, Greg. More awareness and more good data needed.

Thank you, audience, for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Dr Greg Hundley: This program is copyright the American Heart Association, 2020.